EP0127535A2 - Pharmazeutische Zusammensetzungen mit Gehalt an Insulin - Google Patents

Pharmazeutische Zusammensetzungen mit Gehalt an Insulin Download PDF

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Publication number
EP0127535A2
EP0127535A2 EP84401049A EP84401049A EP0127535A2 EP 0127535 A2 EP0127535 A2 EP 0127535A2 EP 84401049 A EP84401049 A EP 84401049A EP 84401049 A EP84401049 A EP 84401049A EP 0127535 A2 EP0127535 A2 EP 0127535A2
Authority
EP
European Patent Office
Prior art keywords
acid
insulin
bile
pharmaceutical composition
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP84401049A
Other languages
English (en)
French (fr)
Other versions
EP0127535A3 (en
EP0127535B1 (de
Inventor
Miriam Kidron
Ehud Ziv
Hanoch Bar-On
Amiram Eldor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hadassah Medical Organization
Original Assignee
Hadassah Medical Organization
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hadassah Medical Organization filed Critical Hadassah Medical Organization
Priority to AT84401049T priority Critical patent/ATE49125T1/de
Publication of EP0127535A2 publication Critical patent/EP0127535A2/de
Publication of EP0127535A3 publication Critical patent/EP0127535A3/en
Application granted granted Critical
Publication of EP0127535B1 publication Critical patent/EP0127535B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • the present invention relates to a pharmaceutical composition containing insulin. More particularly, the present invention relates to a pharmaceutical composition for the oral administration of insulin.
  • Insulin is a medicament particularly useful as a hypoglycaemic agent being widely used by patients suffering from diabetes and is the only treatment for juvenile diabetes mellitus.
  • the insulin pump has been developed in the last decade. This pump, however, also suffers from some of the disadvantages of the daily injection. Since insulin is normally secreted into the portal vein, normally the liver is exposed to a greater insulin concentration than peripheral tissues. Insulin administered via the peripheral venous system to insulin-deficient diabetic patients results in a concentration of insulin in the portal vein almost equal to that in the peripheral circulation. The net result is hypoinsulinemia in the portal vein and the liver and hyperinsulinemia in the peripheral venous system. This may lead to an abnormal pattern of glucose disposal.
  • insulin was used as a model for proteins in general to discover the theoretical question of protein absorption through the intestine and it was found that in the presence of the strong detergent effect of deoxycholic acid and soybean trypsin inhibitor, biologically active macromolecules such as insulin could be effectively absorbed from the intestine.
  • a pharmaceutical composition for rectal administration which comprises insulin, a carrier suiting the composition for rectal administration, and an agent for increasing the rate of absorption of the insulin into the body on rectal administration of the composition, the agent comprising at least one material selected from (a) nonionic polyoxyethylene ether surface active agents having an HLB value of 6 to 19 and wherein the average number of polyoxyethylene units is 4 to 30, (b) anionic surface active agents, (c) cationic surface active agents, (d) ampholytic surface active agents, (e) bile acids and (f) alkali metal salts of bile acids and amounting to 0.001 to 0.5 times the weight of the carrier.
  • U.S. Patents 4434159 and 4164573 there are described similar insulin containing pharmaceutical compositions for rectal administration.
  • compositions for the oral administration of insulin comprising insulin, a bile acid or alkali metal salt thereof, said bile acid being selected from the group consisting of cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3B-monohydroxychloric acid, lithocholic acid, 3a-hydroxy-12-ketocholic acid, 3 ⁇ -hydroxy-12-ketocho1ic acid, l2a-3a-dihydrocholic acid, and ursodesoxycholic acid, and a protease inhibitor, said composition being provided with an enterocoating to assure passage through the stomach and release in the intestine.
  • compositions containing insulin which can be administered orally and which have the same effect as naturally secreted insulin on the blood glucose levels.
  • the insulin administered according to the present invention reaches the intestine and is quickly absorbed in the body through the intestine and through the portal system to the liver. This absorption route is the most convenient way to administer the drug and it resembles the physiological secretion of insulin by the pancreas, thus enabling delicate control of the blood glucose level and the metabolic activities of the liver and the peripheral organs controlled by insulin.
  • Another approach for insulin enhanced activity is the addition of an adjuvant such as choline (which is not a bile salt) to the insulin injections (U.S. patent 2563070).
  • an adjuvant such as choline (which is not a bile salt)
  • choline which is not a bile salt
  • This is totally different from oral administration with bile salts since the bile salts in an oral composition enhance the absorption of insulin from the intestinal luman to the blood circulation while with injectable solutions no such absorption takes place or is necessary and the function of choline which is different structurally and chemically from cholic acid is entirely different in said patent and is intended to delay the insulin absorption.
  • Human insulin including human insulin genetically reproduced or any insulin such as, for example, the insulin obtained from cows (bovine), pigs or whales can be used as the insulin for compositions of this invention.
  • metal complexes of insulin such as the zinc complex of insulin as well as protamine zinc insulin and globin zinc insulin may be also used as the insulin in compositions of this invention.
  • the protease inhibitor used in the compositions of the present invention can be any material which has the ability to inhibit any proteolytic activity.
  • protease inhibitors include d protinin (Trasilol (R) of Bayer), Pentamidine isethionate, antipain, tosylamide-phenylethyl-chloromethyl ketone (TPCK), phenylmethyl sulfonyfluoride (PMSF), pepstatin, trypsin inhibitor, Acetone, Alcohols, guanidium, A 2 -macrogiobulin, TLCK, Chelating agents of Zn, Iodoacetate, a l -antitrypsin, EDTA, Zn, Antithrombin III, leupeptin: Trypsin inhibitor from soy bean, trypsin inhibitor from hen egg white, trypsin inhibitor from chicken egg white, etc.
  • protinin Trasilol (R) of Bayer
  • Pentamidine isethionate tosylamide-phenylethyl-chloromethyl ketone
  • PMSF phenylmethyl
  • protease inhibitors might be toxic in large doses and therefore, if chosen, the use and dosage thereof must be carefully screened and tested.
  • said protease inhibitor is selected from the group consisting of aprotinin, A 2 -macroglobulin, antithrombin III and trypsin inhibitor from soy bean or chicken egg white.
  • the most preferred protease inhibitor agents used in this invention are preferably Trasylol (R) in the amount of 1000 k.i.u./ 100 mg pill, or 3 mg soybean trypsin inhibitor or 10 mg soybean flour.
  • bile acids and alkali metal salts thereof used in the oral compositions of the present invention promote the absorption of the insulin from the intestinal tract and act as carriers therefor, however, it was interesting and surprising to note that deoxycholic acid, which was the acid of choice in the article in Life Sciences, Vol. 31, pp. 2837-2441 (1982) is unsuitable for use in the oral compositions of the present invention because of the damage which it causes to the cells of the intestinal wall.
  • the active concentration of bile acid or salt thereof is about 1-20 mg/nil and preferably about 5-15 mg/pill/one treatment.
  • sodium cholate can simultaneously function both as the bile acid carrier of the insulin and the protease inhibitor agent and thus a composition comprising insulin and sodium cholate in an enteric coating is especially preferred.
  • the amount of insulin in a composition is 20-50u/kg in rats and expected to be about 0.5-3u/kg in humans.
  • Preferred dosages for humans are about 1-2u/kg/treatment with three treatments a day, however sustained release microencapsulation could allow treatment to be reduced to once or twice a day.
  • the enterocoating and possible microencapsulation of the mixture provides protection for the insulin against decomposition in the stomach and for the slow release of the mixture consistuents in the intestinal tract.
  • the enterocoating is carried out by methods known per se in the art, e.g., according to Remington Pharmaceutical Sciences, p. 1614-1615 (1975, 15th Ed. Mack Pub. Co.) and Theory and Practice of Industrial Pharmacy, Lackman, Liberman & Canig, p. 116-117, 371-374 (1976, 2nd Ed.) as is the enteric microencapsulation (Theory and Practice of Industrial Pharmacy ibid, pp. 420-438).
  • One of the findings of the present invention is that there is different rate of absorption of the different constituents of the present composition from the intestinal lumen into the blood stream.
  • the absorption of the bile acid is very fast, e.g., more than 50% of cholic acid is absorbed during 30 minutes while only 5-10% of the insulin is absorbed during 60 minutes.
  • a drug regimen involving ingestion of a pair of pills at spaced intervals e.g., a second pill containing a higher concentration of bile acid to be taken half an hour after the first pill is contemplated as is microencapsulation of different constituents with spaced time release coatings to enhance the absorption of the insulin into the system.
  • An enterocoated capsule was prepared for oral administration of insulin to a diabetic dog.
  • Table I shows Plasma 1R1 levels and glucose levels with administration.
  • a solution was prepared for direct intestinal administration of 0.5 ml in final volume.
  • Enterocoating provides the sufficient shelter against the destruction of the insulin in the stomach and delays its effect for one hour in the dog.
  • compositions according to the present invention are hereinafter set forth in tabular form:
  • the dissolution of the tablets was then tested according to USP XX.
  • the tablets were found to be stable for two hours in gastric juices. When they are then transferred to intestinal juices, they dissolve there in less than 1/2 an hour.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Botany (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP84401049A 1983-05-23 1984-05-21 Pharmazeutische Zusammensetzungen mit Gehalt an Insulin Expired - Lifetime EP0127535B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT84401049T ATE49125T1 (de) 1983-05-23 1984-05-21 Pharmazeutische zusammensetzungen mit gehalt an insulin.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL68769A IL68769A (en) 1983-05-23 1983-05-23 Pharmaceutical compositions containing insulin for oral administration
IL68769 1983-05-23

Publications (3)

Publication Number Publication Date
EP0127535A2 true EP0127535A2 (de) 1984-12-05
EP0127535A3 EP0127535A3 (en) 1987-01-14
EP0127535B1 EP0127535B1 (de) 1990-01-03

Family

ID=11054289

Family Applications (1)

Application Number Title Priority Date Filing Date
EP84401049A Expired - Lifetime EP0127535B1 (de) 1983-05-23 1984-05-21 Pharmazeutische Zusammensetzungen mit Gehalt an Insulin

Country Status (8)

Country Link
US (1) US4579730A (de)
EP (1) EP0127535B1 (de)
JP (1) JPH0678238B2 (de)
AT (1) ATE49125T1 (de)
CA (1) CA1223200A (de)
DE (1) DE3480903D1 (de)
DK (1) DK167240B1 (de)
IL (1) IL68769A (de)

Cited By (25)

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US4579730A (en) * 1983-05-23 1986-04-01 Hadassah Medical Organization Pharmaceutical compositions containing insulin
FR2619717A1 (fr) * 1987-09-02 1989-03-03 Medibrevex Nouvelles formes galeniques d'insuline pour administration par voie per- et sublinguale
US4849227A (en) * 1986-03-21 1989-07-18 Eurasiam Laboratories, Inc. Pharmaceutical compositions
EP0302445A3 (en) * 1987-08-07 1990-04-25 The Protor Co. A novel hypoglycemic and growth-promoting agent
EP0462071A1 (de) * 1990-06-15 1991-12-18 Sandoz Ltd. Pharmazeutische Somatostatin enthaltende Zusammensetzung mit verbesserter Resorption, seine Herstellung und Verwendung
FR2668933A1 (fr) * 1990-06-15 1992-05-15 Sandoz Sa Composition pharmaceutique a base de somatostatine.
US5122376A (en) * 1989-05-12 1992-06-16 Isf Societa Per Azioni Calcitonin gene related peptide
EP0509335A1 (de) * 1991-04-12 1992-10-21 ALFA WASSERMANN S.p.A. Magensaftstabile pharmazeutische Formulierungen zur Oral Verbreichung von Gallensäuren
EP0510404A1 (de) * 1991-04-12 1992-10-28 ALFA WASSERMANN S.p.A. Gallensäuresalze enthaltende magenstabile pharmazeutische Zusammensetzung zur oralen Verabreichung
US5183802A (en) * 1987-11-13 1993-02-02 Isf Societa Per Azioni Pharmaceutical compositions for intranasal administration of calcitonin
WO1993011799A1 (en) * 1991-12-18 1993-06-24 Pfizer Inc. Soybean protein or hydrolyzates in pharmaceutical compositions to protect bioactive peptides from enzymatic inactivation
WO1994021286A1 (en) * 1993-03-19 1994-09-29 Fjellestad Paulsen Anne Composition for oral administration of peptides
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WO1995007931A1 (en) * 1993-09-17 1995-03-23 Novo Nordisk A/S Acylated insulin
WO1996006635A1 (en) * 1994-08-31 1996-03-07 Cortecs Limited Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound
WO1997021448A1 (en) * 1995-12-13 1997-06-19 Dullatur Limited A calcitonin preparation
RU2117488C1 (ru) * 1997-07-30 1998-08-20 Институт нефтехимического синтеза им.А.В.Топчиева РАН Твердое инсулинсодержащее лекарственное средство
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WO2001039794A1 (fr) * 1999-11-30 2001-06-07 Oao 'quantum Satis' Medicament a usage peroral contenant de l'insuline et procede de fabrication correspondant
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US6869930B1 (en) 1993-09-17 2005-03-22 Novo Nordisk A/S Acylated insulin
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US4849227A (en) * 1986-03-21 1989-07-18 Eurasiam Laboratories, Inc. Pharmaceutical compositions
EP0302445A3 (en) * 1987-08-07 1990-04-25 The Protor Co. A novel hypoglycemic and growth-promoting agent
FR2619717A1 (fr) * 1987-09-02 1989-03-03 Medibrevex Nouvelles formes galeniques d'insuline pour administration par voie per- et sublinguale
EP0306421A1 (de) * 1987-09-02 1989-03-08 Medibrevex Sa Galenische Insulinformen zur per- und sublingualen Verabreichung
US5183802A (en) * 1987-11-13 1993-02-02 Isf Societa Per Azioni Pharmaceutical compositions for intranasal administration of calcitonin
US5122376A (en) * 1989-05-12 1992-06-16 Isf Societa Per Azioni Calcitonin gene related peptide
FR2668933A1 (fr) * 1990-06-15 1992-05-15 Sandoz Sa Composition pharmaceutique a base de somatostatine.
FR2663227A1 (fr) * 1990-06-15 1991-12-20 Sandoz Sa Compositions pharmaceutiques de somatostatine a biodisponibilite amelioree.
GB2244918B (en) * 1990-06-15 1994-06-15 Sandoz Ltd Pharmaceutical compositions comprising somatostatin and cholanic acid derivatives
EP0462071A1 (de) * 1990-06-15 1991-12-18 Sandoz Ltd. Pharmazeutische Somatostatin enthaltende Zusammensetzung mit verbesserter Resorption, seine Herstellung und Verwendung
EP0509335A1 (de) * 1991-04-12 1992-10-21 ALFA WASSERMANN S.p.A. Magensaftstabile pharmazeutische Formulierungen zur Oral Verbreichung von Gallensäuren
EP0510404A1 (de) * 1991-04-12 1992-10-28 ALFA WASSERMANN S.p.A. Gallensäuresalze enthaltende magenstabile pharmazeutische Zusammensetzung zur oralen Verabreichung
WO1993011799A1 (en) * 1991-12-18 1993-06-24 Pfizer Inc. Soybean protein or hydrolyzates in pharmaceutical compositions to protect bioactive peptides from enzymatic inactivation
US6153592A (en) * 1992-11-09 2000-11-28 Port Systems, Llc Enhancing the bioavailability of proteolytically labile therapeutic agents
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WO1995006463A1 (en) * 1993-09-01 1995-03-09 Pfizer Inc. Pharmaceutical compositions containing anionic surfactants
WO1995007931A1 (en) * 1993-09-17 1995-03-23 Novo Nordisk A/S Acylated insulin
US5750497A (en) * 1993-09-17 1998-05-12 Novo Nordisk A/S Acylated insulin
US6869930B1 (en) 1993-09-17 2005-03-22 Novo Nordisk A/S Acylated insulin
EP1132404A3 (de) * 1993-09-17 2002-03-27 Novo Nordisk A/S Acyliertes Insulin
US5853748A (en) * 1994-08-31 1998-12-29 Cortecs (Uk) Limited Pharmaceutical compositions
WO1996006635A1 (en) * 1994-08-31 1996-03-07 Cortecs Limited Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound
WO1997021448A1 (en) * 1995-12-13 1997-06-19 Dullatur Limited A calcitonin preparation
US6638909B1 (en) 1996-11-01 2003-10-28 Ethicon, Inc. Wound healing compositions containing alpha-1-antitrypsin
RU2117488C1 (ru) * 1997-07-30 1998-08-20 Институт нефтехимического синтеза им.А.В.Топчиева РАН Твердое инсулинсодержащее лекарственное средство
WO2001039794A1 (fr) * 1999-11-30 2001-06-07 Oao 'quantum Satis' Medicament a usage peroral contenant de l'insuline et procede de fabrication correspondant
US7651995B2 (en) 2003-04-15 2010-01-26 Axcess Limited Absorption enhancers such as e.g. BHT, BHA or propyl gallate
US8314058B2 (en) 2003-04-15 2012-11-20 Axcess Limited Uptake of macromolecules
WO2011015984A1 (en) 2009-08-03 2011-02-10 Cera-Med Kft. Orally administerable pharmaceutical preparation containing insulin
US20120129769A1 (en) * 2009-08-03 2012-05-24 Szilvassy Zoltan Orally administerable pharmaceutical preparation containing insulin
CN102791282A (zh) * 2009-08-03 2012-11-21 赛拉医药有限责任公司 可口服给予的含有胰岛素的药物制剂
US10350169B2 (en) 2014-10-31 2019-07-16 University Of Utah Research Foundation Compositions and methods for bile acid particles

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CA1223200A (en) 1987-06-23
EP0127535A3 (en) 1987-01-14
DE3480903D1 (de) 1990-02-08
IL68769A0 (en) 1983-09-30
DK229484A (da) 1984-11-24
US4579730A (en) 1986-04-01
IL68769A (en) 1986-02-28
ATE49125T1 (de) 1990-01-15
JPS6069028A (ja) 1985-04-19
JPH0678238B2 (ja) 1994-10-05
DK167240B1 (da) 1993-09-27
DK229484D0 (da) 1984-05-09
EP0127535B1 (de) 1990-01-03

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